Carrageenan viscoelastics for ocular surgery

ABSTRACT

Disclosed are carrageenan-based transitional viscoelastics that will induce little or no IOP spike when left in the eye at the close of surgery thereon. Drug delivery systems for delivering therapeutic agents during post-operative recovery stages are also disclosed.

FIELD OF THE INVENTION

[0001] The present invention relates to the field of viscous andviscoelastic materials suitable for use in surgical procedures. Inparticular, transitional viscoelastics (having non-shear relatedvariable viscosities) comprising carrageenans, which may be left iiisitu at the close of surgery, are disclosed. Methods of usingtransitional viscoelastics in surgery, especially ophthalmic surgery arealso disclosed.

BACKGROUND OF THE INVENTION

[0002] Viscous or viscoelastic agents used in surgery may perform anumber of different functions, including without limitation maintenanceand support of soft tissue, tissue manipulation, lubrication, tissueprotection, and adhesion prevention. It is recognized that the differingrheological properties of these agents will necessarily impact theirability to perform these functions, and, as a result, their suitabilityfor certain surgical procedures. See, for example, U.S. Pat. No.5,273,056.

[0003] Cataracts are opacities of the ocular lens which generally arisein the elderly. In order to improve eyesight, the cataractous lens issurgically removed and an artificial intraocular lens is inserted in itsplace. During these surgical procedures, viscoelastic materials aretypically injected in the anterior chamber and capsular bag to preventcollapse of the anterior chamber and to protect tissue from damageresulting from physical manipulation.

[0004] A number of viscous or viscoelastic agents (hereinafter “agents”)are known for ophthalmic surgical use. For example, Viscoat® (AlconLaboratories, Inc.) which contains sodium hyaluronate and chondroitinsulfate; Healon® and Healon® GV (Pharmacia Corp.), Amvisc® Regular andAmvisc® Plus (IOLAB), and Vitrax® (Allergan) all of which contain sodiumhyaluronate; and Cellugel® (Alcon) which containshydroxypropylmethylcellulose (HPMC) are all useful in cataract surgery.They are used by the skilled ophthalmic surgeon for several purposes:maintenance of the anterior chamber of the eye and protection ofophthalmic tissues during surgery, particularly corneal endothelialcells, and as an aid in manipulating ophthalmic tissues.

[0005] While all of the agents described above may be used duringcataract surgery, each has certain recognized advantages anddisadvantages. See, U.S. Pat. No. 5,273,056. Generally, however, allsuch agents having sufficient viscosity and pseudoplasticity to beuseful in ophthalmic surgery will, if left in the eye at the close ofsurgery, result in a transient increase in intraocular pressure (“IOP”)known as an “IOP spike.” (See, Obstbaum, Postoperative pressureelevation. A rational approach to its prevention and management, J.Cataract Refractive Surgery 18:1 (1992).) The pressure increase has beenattributed to the agent's interference with the normal outflow ofaqueous humor through the trabecular meshwork and Schlemm's canal. (See,Berson et al., Obstruction of Aqueous Outflow by Sodium Hyaluronate inEnucleated Human Eyes, Am. J. Ophthalmology 95:668 (1983); Olivius etal., Intraocularpressure after cataract surgery with Healon®, Am.Intraocular Implant Soc. J. 11:480 (1985); Fry, Postoperativeintraocular pressure rises: A comparison of Healon, Amvis, and Viscoat,J. Cataract Refractive Surgery 15:415 (1989).) IOP spikes, depending ontheir magnitude and duration, can cause significant and/or irreversibledamage to susceptible ocular tissues, including, without limitation, theoptic nerve.

[0006] Thus, the ease with which an agent can be removed from thesurgical site, typically by aspiration, has traditionally beenconsidered an important characteristic in the overall assessment of theagent's usefulness in cataract surgery. By removing the agent before theclose of surgery, the surgeon hopes to minimize or avoid any significantIOP spike. Unfortunately, however, removal of agents which arerelatively dispersive (as opposed to cohesive) or which adhere to theocular tissue is often difficult and may cause additional trauma to theeye.

[0007] Exogenous dilution of the viscoelastic has been suggested toalleviate IOP spikes. See U.S. Pat. No. 4,328,803. Depending, however,on the particular viscoelastic and the surgical technique employed, IOPspike may still be a problem. More recently, it has been suggested thatthe administration of degradative agents to break down conventionalviscous or viscoelastic agents in the eye can reduce or avoid theoccurrence of IOP spikes. See, e.g., U.S. Pat. No. 5,792,103. Such anapproach requires not only the administration of a second, enzymaticagent into the eye, the biocompatibility of which must be assured; butalso means for adequately mixing the two agents in a special apparatus.

[0008] Viscoelastics have also been promoted as drug delivery devicesfor pharmaceutical agents which are administered when the viscoelasticsare applied during surgery. For example, U.S. Pat. No. 5,811,453 (Yanniet al.) discloses viscoelastics containing anti-inflammatory compoundsand methods of using these enhanced viscoelastics in cataract surgery.While this approach may ameliorate ocular inflammation resulting fromsurgical trauma, such an approach still possesses the significantlimitation of presenting IOP spike problems, as described above.Consequently, these enhanced viscoelastics still need to be aspiratedout at the close of surgery.

[0009] There is, therefore, a need for an improved means for reducing oravoiding IOP spikes associated with the use of conventional viscous orviscoelastic agents in ophthalmic surgery, especially cataract surgery.More specifically, we conceived the need for an improved viscous orviscoelastic agent having a variable or transitional viscosity such thatit will, without the addition of degradation agents, becomesubstantially less viscous after its purpose has been served in surgery,such agents being hereinafter referred to as transitional viscoelastics.Such transitional viscoelastics may then be left by the surgeon to beeliminated gradually from- the surgical site-by the body's naturalprocesses without creating a dangerous IOP spike.

[0010] Transitional viscosities are known to occur in certain agentssystems. In the ophthalmic field, systems are known in which a liquidforms a gel after application to the eye. For example, such gelationsmay be triggered by a change in pH. See, Gurney et al., “The Developmentand Use of In Situ Formed Gels, Triggered by pH” Biopharni. Ocul. DrugDelivery, (1993) pp. 81-90. Temperature sensitive gelation systems havealso been observed for certain ethyl (hydroxyethyl) cellulose ethers(EHECs) when mixed with particular ionic surfactants at appropriateconcentrations. See, Carlsson et al., “Thermal Gelation of NonionicCellulose Ethers and Ionic Surfactants in Water” Colloids Surf., volume47, pages 147-65 (1990) and for systems of pure methylethyl cellulose,U.S. Pat. No. 5,618,800 (Kabra et al.)) Likewise, gellan gum (Gelrite®)is known to form a gel on contact with specific cations. Greaves et al.,“Scintigraphic Assessment of an Ophthalmic Gelling Vehicle in Man andRabbit,” Curr. Eye Res., volume 9, page 415 (1990). Gellan systems havebeen suggested for use as a vehicle for ophthalmic medications (Rozieret al., “Gelrite: A Novel, Ion-Activated, In Situ Gelling Polymer forOphthalmic Vehicles. Effect on Bioavailability of Timolol,” Int. JPharm., volume 57, page 163 (1989)), and one gellan system is currentlybeing marketed with timolol, a beta blocker, as a glaucoma medication.Carrageenans also have been suggested for use as a delivery vehicle forophthalmic drugs. See, e.g. U.S. Pat. Nos. 5,403,841 and 5,965,152, thecontents of both of which are by this reference incorporated herein.U.S. Pat. No. 5,403,841 and EPO 424043 disclose ophthalmic carrageenancompositions which transition from liquid to gel when topically appliedto the eye. Finally, it is known that carrageenans can be tailored toadjust their viscosity transitions to different temperature ranges.(See, Verschueren et al. “Evaluation of various carrageenans asophthalmic viscolysers” STP Phanna Sci, volume 6, pages 203-210 (1996),and Picullel et al., “Gelling Carrageenans,” Food Polysaccharides andTheir Applications, Ed: Stephen, A.M., Marcel Dekker:New York, volume67, pages 204-44 (1995).) Kappa-carrageenans, for example, arepolysaccharides which display a temperature dependent conformationwherein at high temperature the molecules exist as random coils. As thetemperature is lowered, the chains associate into double helices, and,depending on the amount of potassium (K⁺) in the solution, the doublehelices then self-associate into a three dimensional network. The gelformed by potassium cross-linked kappa-carrageenan is, unfortunately,very brittle, resembling the gels formed by calcium cross-linkedalginate and pectin. All of these gels also exhibit syneresis, a processwherein the formation of the gel is so favored that the solvent(physiologic aqueous media here) is forced out from the gel network.

[0011] The use of a transitional viscosity viscoelastic agent as aneffective surgical tool, however, especially in ophthalmic surgery, hasneither been disclosed or suggested in the art. To be effective for useas an ophthalmic surgical tool, the agent, in addition to having thedesired initial and transitional viscosities over the prescribedtemperature range, would need to meet the following requirements:physiologically acceptable osmolarity and pH; relatively short viscositytransition time; clear (without turbidity); biocompatible; andsterilizable. The transitional viscoelastics of the present inventionare believed to satisfy these requirements

SUMMARY OF THE INVENTION

[0012] The present invention is directed to improved viscous orviscoelastic agents for use in surgical procedures, especiallyophthalmic surgical procedures. The improved agents of the presentinvention are stable, transitional viscous or viscoelastic carrageenansolutions suitable for use in ophthalmic surgery, which maintain highviscosity during the surgical procedure, but rapidly lose viscosityafter the close of surgery. This rapid loss of viscosity effectivelyreduces or avoids the occurrence of dangerous IOP spikes, and obviatesthe need for active removal at the end of the surgical procedure.

[0013] Appreciating that the surface temperature of the eye tissuesduring surgery will approximate surgical room temperature, we havediscovered stable agents that will maintain suitable viscosity at thattemperature, but will rapidly lose viscosity at a slightly highertemperature (i.e., body temperature). The loss of viscosity, whichoccurs without the addition of a degradation agent, results from thewarming of the eye back to body temperature after the surgery iscomplete.

DETAILED DESCRIPTION OF THE DRAWINGS

[0014]FIG. 1 is graph depicting the transitional viscosity ofCarrageenan (80% kappa/20% iota) solutions of the present inventionhaving different potassium concentrations, over a range of temperatures.

[0015]FIG. 2 is graph depicting the transitional viscosity ofCarrageenan (80% kappa/20% iota) solutions of the present inventioncompared to commercially available viscoelastic products.

[0016]FIG. 3 is graph depicting viscosity versus shear rate forCarrageenan (80% kappa/20% iota) solutions of the present invention.

[0017]FIG. 4 is a graph depicting viscosity versus shear rate forautoclaved and unautoclaved Carrageenan (80% kappa/20% iota) solutionsof the present invention.

[0018]FIG. 5 is a graph depicting viscosity versus temperature for 0.8%Carrageenan solutions of the present invention with variable kappa/iotaratios.

[0019]FIG. 6 is a graph depicting data from a constant stressoscillation experiment using 0.7% Carrageenan solutions of the presentinvention.

[0020]FIG. 7 is a graph depicting data from a constant frequencyoscillation experiment using 0.7% Carrageenan solutions of the presentinvention.

DETAILED DESCRIPTION OF THE PRESENT INVENTION

[0021] The present invention is directed to substantially stable,transitional viscoelastic materials, compositions and methods of use.

[0022] The primary use of the transitional viscoelastics is in surgicalapplications where the transitional viscoelastic is applied duringsurgery in its more viscous state and, following surgery, losessubstantial viscosity in situ. A preferred use of the transitionalviscoelastics is in cataract surgery, where the viscoelastic isinstilled in the anterior chamber of the eye to maintain the dome andprotect the exposed tissues. Following surgery, the viscoelastic isheated by the body to ambient body temperature, loses its viscosity, andis more readily removed (than non-transitional viscoelastics) by theeye's processes. The major advantage of this preferred use is theavoidance of the IOP spike present in other systems. Thus, anotheradvantage of this use is that it allows the surgeon the traditionaladvantages of a viscoelastic without the disadvantage of having toaspirate the viscoelastic out of the surgical site following completionof the surgery. As stated above, such aspiration is time consuming andpresents additional risk to the patient.

[0023] The transitional viscoelastics of the present invention aretypically modified viscoelastics exhibiting a viscosity loss of 80% ormore, when such materials undergo a temperature change of from aboutroom temperature or surgical temperature (approximately 17-26° C.) toabout body temperature (approximately 35-38° C.).

[0024] The transitional property of the present invention viscoelasticsis preferably reversible. The reversible viscosity property of thepreferred embodiments allows the transitional viscoelastics to be heatedprior to use, e.g., heat sterilization, and then recooled for surgicalapplication.

[0025] While bound by no theories, we postulate that the transitionalviscoelastic character of the compositions of the present invention maybe attributable to physical associations between relatively lowmolecular weight molecules resulting in a viscosity beyond what would beexpected from such low molecular weight molecules at a givenconcentration. The viscosity of the presently claimed viscoelasticsolution goes through a transition in the intraocular environment andbecomes a free flowing aqueous solution. As a result, the subjectviscoelastic solution can pass through the trabecular meshwork of theeye, resulting in its excretion from the anterior segment, with no orsignificantly reduced intraocular pressure spike.

[0026] Kappa-carrageenan is a polysaccharide which displays atemperature dependent conformation wherein at high temperature themolecules exist as random coils. As the temperature is lowered, thechains associate into double helices, and, depending on the amount of K⁺in the solution, the double helices then self-associate into a threedimensional network. The gel formed by potassium cross-linkedkappa-carrageenan, while useful as a transitional viscoelastic, isrelatively brittle and elastic compared to commercially availableviscoelastics, and resembles the gels formed by calcium cross-linkedalginate and pectin. All of these gels also exhibit a degree ofsyneresis, a process wherein the formation of the gel is so favored thatthe solvent (physiologic aqueous media here) is forced out from the gelnetwork.

[0027] Surprisingly, it has been discovered that the previouslydescribed deficiencies of kappa carrageenan as a transitionalviscoelastic may be overcome by blending it with one or more relatedpolymers, preferably being pharmaceutically acceptable sulfatedpolysaccharides. In a preferred embodiment, kappa- and iota-carrageenanare mixed in order to reduce syneresis and the brittle nature of thekappa-carrageenan gels. The iota-carrageenan competes with thekappa-carrageenan for potassium, resulting in a more viscous and lessbrittle gel, while retaining a desirable transitional profile.

[0028] The kappa carrageenan and other sulfated polysaccharides of thepresent invention will have the weight average molecular weight rangesset forth in the following table: Preferred MW Polysaccharide MW Range(M_(W)) Range (M_(W)) Kappa-Carrageenan 25-900 kDa 50-400 kDaIota-Carrageenan 100-3,000 kDa 400-700 kDa Chondroitin sulfate 10-100kDa 20-60 kDa Heparin 2-50 kDa 6-30 kDa

[0029] Preferred concentrations for the kappa-carrageenan constituent,alone or mixed with another sulfated polysaccharide such asiota-carrageenan, fall in the range of 0.3 to 1.5 weight percent.Overall viscosity is directly dependent on the concentration used. Thecarrageenans, both kappa and iota, are commercially available from FMCCorporation, Food Ingredients Division, Rockland, Me.

[0030] For mixtures, the ratio of kappa to iota will preferably be inthe range of 40 to 90% kappa to 10 to 60% iota (i.e. from about 4:6 toabout 9:1) to preserve the beneficial transitional properties of thekappa constituent and the viscous gel imparting properties of the iotaconstituent. The potassium-level should not exceed 0.10% on aweight-to-volume basis in an aqueous media based on balanced saltsolution with citrate/acetate buffer or a NaCl solution with phosphatebuffers. The level of potassium will modulate the transitiontemperature, and should be chosen so that the transition is essentiallycomplete by 35 degrees Celsius.

[0031] The carrageenan solutions. of the present invention areautoclavable at exposure for at least 60 minutes, without appreciablereduction of their transitional viscoelastic character. Such solutionswill preferably lose at least 90 percent of their pre-transitionviscosity and most preferably at least 99% upon heating through thetransition. As described herein, the transition temperature range willdepend upon and may be controllably shifted by varying the potassiumlevel. Preferred viscosity transition ranges, however, will be fromabout 17-26° C. on the lower end, to about 35-38° C. on the upper end.Most preferred is a transition temperature range from about 25° C. toabout 37° C.

[0032] A unique aspect of the transitional viscoelastics of the presentinvention is that they possess a variable transition temperature range.The transition temperature is affected, and thus controllable, by theamount of potassium present. Furthermore, the magnitude of thetransition, in terms of viscosity loss through the transition, is muchgreater than has been reported with hydrophobically modified materials.These materials are also steam autoclavable, and achieve usefulviscosities with relatively short polysaccharide chains andconcentrations of 1% or less.

[0033] The following exemplify some of the preferredkappa-/iota-carrageenan transitional viscoelastics of the presentinvention.

EXAMPLE 1

[0034] Solutions of 0.5 wt % carrageenan (80% kappa-/20% iota-) weremade in PBS with 0% to 0.070% KCl. These samples were heated to abovethe transition temperature and hot filtered through a 5 micron filter.The solutions were cooled and then subjected to 50 passes through a dualhub syringe connector. Rheological data was then collected, andviscosity versus temperature data is shown in FIG. 1. The figure showsthat the effect of increasing levels of potassium is to increase thepre-transition viscosity and to increase the transition temperature.Potassium ions appear to have little or no effect on the post-transitionviscosity.

EXAMPLE 2

[0035] Solutions with a total of 80% kappa-carrageenan and 20%iota-carrageenan were made in phosphate buffered saline. The totalsolids of the solutions ranged from 0.6 wt % to 0.8 wt %. FIG. 2 showsthe viscosity versus temperature Theological curves for these mixtures.The curves for PROVISC® product and for VISCOAT® product are alsoincluded as controls. The figure shows that increased solids contentincreases both the pre-transition viscosity and the transitiontemperature itself. The 0.7 wt % and the 0.8 wt % samples are viscositymatched to the VISCOAT® and PROVISC® curves at 28° C., respectively.PROVISC® and VISCOAT® lose about 33% of their viscosity over the rangeshown in the figure. In marked contrast, the 0.7 and 0.8% carrageenangels lose more than 99.9% of their viscosity over the transition rangefrom approximately 34° C. to approximately 40° C.

EXAMPLE 3

[0036] Solutions of carrageenan (80% kappa-/20% iota) were made at 0.5%,0.6%, 0.7% and 0.8% in PBS and hot filtered and homogenized as above.FIG. 3 shows the viscosity versus shear rate dependencies for thesesamples. The figure shows a general increase in viscosity with increasedlevels of carrageenan in the solution. Interestingly, the viscosity ofthe 0.5% solutions are much lower than the other samples. The 0.5%samples did not gel to the extent of the higher weight percent samples.

EXAMPLE 4

[0037] A solution of a 0.9 wt % carrageenan (80% kappa-/20% iota-) wasprepared in PBS and hot filtered and homogenized as above. This solutionwas split into two samples, one of which was subjected 30 minutesexposure at approximately 121° C. in a steam autoclave. FIG. 4 showsthese two samples to display little variation in their rheologicalbehavior as evidenced by the plot of viscosity versus shear rate. Thecurve for the autoclaved sample is generally below the control curve;however, the Theological properties of the autoclaved material are stillin the very useful range.

EXAMPLE 5

[0038] Solutions with a total of 0.8 wt % carrageenan were made inphosphate buffered such that the ratio of kappa-carrageenan toiota-carrageenan included solutions with 0%, 20%, 40%, 60%, 80% and 100%of kappa-, with the remainder being the percent of iota-. FIG. 5 showsthe viscosity versus temperature Theological data in the pre-transition,the transition, and the post-transition regions. The data support theidea that pre-transition viscosity is higher with higher percentages ofiota-carrageenan. The data also support the idea that the transitiontemperature is lower with higher percentages of kappa-carrageenan andthat the more iota- in the mixture, the more drawn out the later stagesof the transition are. Based upon this figure, it is felt that too muchiota raises the transition temperature and causes a tailing off of theviscosity at the end of the transition region. Thus, the iota contentpreferably should be less than 60 percent to preserve the transitiontemperature of the kappa- portion of the mixture. The iota contentshould further be minimized to reduce the tailing off of the viscosityat the end of the transition. However, the iota- content makes the gelmore viscous and less elastic, or brittle, in nature. A balance betweenkappa- and iota- will depend on the total solids content used. At thistotal concentration, the best gels were produced at 60% kappa- and 40%iota-.

EXAMPLE 6

[0039] Samples of carrageenan at 0.7% solids were made with 50% and 100%kappa- were made in PBS and hot filtered and homogenized as above. FIG.6 shows an oscillatory experiment performed at constant stress over alarge frequence range. At a frequence of 1.29 Hz, the ratio of G″ to G′,in percent form, was shown to be 12.4% for the 100% kappa- and 23.4% forthe 50% kappa-. This result shows that the gel with the mix of kappa-and iota- displays more viscous (G″) character than the 100% kappa-.

EXAMPLE 7

[0040] Samples of carrageenan at 0.7% solids were made with 50%, 60% and100% kappa- were made in PBS and hot filtered and homogenized as above.FIG. 7 shows an oscillatory experiment performed at constant frequencyover a large strain range. At a strain of 0.01, the ratio of G″ to G′,in percent form, was shown to be 8.9%, 20.0%, and 22.5% for the 100%,60% and 50% samples, respectively. This data also shows that theaddition of iota- is directly related to the increase in viscousbehavior and the decrease in elastic behavior.

[0041] Alternatively, the transitional viscoelastics of the presentinvention may comprise combinations of chondroitin sulfate and atransitional viscoelastic agent or agents.

[0042] The primary advantage of combining chondroitin sulfate withtransitional viscoelastic agent lies in the ability of chondroitinsulfate to coat and protect biological tissues. In particular, theability of chondroitin sulfate to coat the interior tissues of the eyeduring ocular surgery gives added protection. For example, duringcataract surgery, chondroitin sulfate can coat and protect the cornealendothelium during the phacoemulsification process, which exposes theinterior tissues of the eye to high ultrasound power, which can causetissue damage. The corneal endothelium is especially important to visionsince this layer of cell is vital in regulation of corneal hydrationlevel and maintenance of the stable refractive power of the cornea.Since this tissue is not regenerated, damage to the corneal epithelialcell can cause a permanent loss in vision. As such, protection of thecorneal endothelium is, therefore, also vital to a favorable outcome tocataract surgery.

[0043] Surprisingly, it has been discovered that the previouslydescribed deficiencies of kappa-carrageenan as a transitionalviscoelastic may be overcome by blending it with other sulfatedpolysaccharides, such as chondroitin sulfate and heparin. While bound byno theories, it is believed that the sulfated polysaccharide competeswith the kappa-carrageenan for potassium via its sulfate groups,resulting in a more viscous and less brittle gel. Therefore, in the caseof transitional viscoelastics based on kappa-carrageenan, an additionaladvantage in the use of chondroitin sulfate is found beyond the abilityof chondroitin sulfate to coat and protect biological and ocular tissuesmentioned above.

[0044] Therefore, the preferred transitional viscoelastics of thepresent invention will be mixtures of chondroitin sulfate andtransitional viscoelastic materials, such as, kappa-carrageenan alone oradmixed with iota-carrageenan. The transitional viscoelastic agents willpreferably have molecular weights from about 50,000 Daltons to about400,000 Daltons (weight average molecular weight). Preferredconcentrations for the kappa-carrageenan component, fall in the range ofabout 0.3 to about 1.5 weight percent. While the preferred concentrationof chondroitin sulfate in these transitional viscoelastic formulationsis from about 0.5 to about 4%. Overall viscosity is directly dependenton the concentration used.

[0045] The viscosities of the transitional viscoelastic formulationsbased on kappa-carrageenan in combination with chondroitin sulfate arealso modulated by the presence of potassium ion. The potassium levelshould not exceed 0.10% on a weight to volume basis in an aqueous mediabased on balanced salt solution with citrate/acetate buffer or a NaClsolution with phosphate buffers. The level of potassium will modulatethe transition temperature, and should be chosen so that the transitionto minimum viscosity is essentially complete by 35° C.

[0046] Chondroitin sulfate is commercially available from Seika GakuCorporation, Tokyo, Japan.

[0047] The effect of adding chondroitin sulfate to thesekappa-carrageenan formulations, i.e. thereby increasing the overallconcentration, is to reduce the elastic character as stated above.However, chondroitin sulfate will also provide small increases inpre-transition viscosity and small decreases in the transitiontemperature.

[0048] The following exemplify some of the preferredkappa-carrageenan/chondroitin sulfate embodiments of the presentinvention.

EXAMPLE 8

[0049] Solutions of 0.7-wt % kappa-carrageenan were made in phosphatebuffered saline (PBS) with 0%, 0.2, 0.4, 0.7 and 0.8% chondroitinsulfate. These samples were heated to above the transition temperatureand hot filtered through a 5-micron filter and transferred to syringes.The solutions were cooled and then subjected to 150 passes through adual hub syringe connector. Rheological data was then collected, andviscosity versus temperature data is shown in FIG. 8. The figure showsthat the effect of increasing levels of chondroitin sulfate is toessentially maintain the pre-transition viscosity and to decrease thetransition temperature. Chondroitin sulfate appears to have little or noeffect on the post-transition viscosity.

EXAMPLE 9

[0050] Solutions with kappa-carrageenan/chondroitin sulfate levels of0.4%/0.5%, 0.5%/0.4%, 0.6/0.3% and 0.7%/0.2%, such that each had a totalviscoelastic content of 0.9% were made in phosphate buffered saline(PBS). These samples were heated to above the transition temperature andhot filtered through a 5-micron filter and transferred to syringes. Thesolutions were cooled and then subjected to 150 passes through a dualhub syringe connector. Rheological data was then collected, andviscosity versus temperature data is shown in FIG. 8. The figure showsthat decreasing the ratio of kappa-carrageenan of chondroitin sulfatedramatically reduced the pre-transition viscosity and transitiontemperature. The 0.5% kappa-/0.4% chondroitin sulfate formulation was aviscoelastic gel rather than a brittle gel. In the absence ofchondroitin sulfate, 0.4% and 0.5% kappa-carrageenan form brittle gels.

EXAMPLE 10

[0051] In order to quantify the effect of chondroitin sulfate on theviscous and elastic nature kappa-carrageenan/chondroitin sulfateviscoelastic formulations, oscillatory rheology was carried out. Asdemonstrated in the table below, the complex viscosity ofcarrageenan/chondroitin sulfate formulations (in this case having a 0.9wt. % total solids content) decreases as the proportion ofkappa-carrageenan in the formulation is decreased. Also the in the tablebelow is a calculation for G″/(G′+G″)×100%, where G″ is the viscousmodulus and G′ is the elastic modulus. This constant frequency (1.3 Hz)experiment is carried out at 0.01 strain. The calculation shows that theviscous nature of the gel increased as the proportion of chondroitinsulfate in the mixture is increased.

[0052] Table—Calculation of Complex Viscosity from Oscillatory RheologyExperiment Complex Viscosity: % Formulation Composition ViscousCharacter = % Kappa-carrageenan % Chondroitin Sulfate {G“/(G‘ + G”)} ×100 0.4 0.5 61% 0.5 0.4 33% 0.6 0.3 11.5 0.7 0.2 11.0

[0053] The 0.7% kappa-/0.2% chondroitin and 0.6% kappa-/0.3% chondroitinformulations show about 11% viscous character; however, when theformulation contains 0.5% kappa-/0.4% chondroitin sulfate, the viscouscomponent rises to 33%. Finally, when the formulation contains 0.4%kappa-/0.5% chondroitin sulfate, the viscous component rises to 61%.

[0054] Those skilled in the art will appreciate that the suitability ofa given transitional viscoelastic for a particular step in a surgicalprocedure will depend upon such things as the viscoelastic'sconcentration, average molecular weight, viscosity, pseudoplasticity,elasticity, rigidity, adherence (coatability), cohesiveness, molecularcharge, and osmolality in solution. The viscoelastic's suitability willdepend further on the function(s) which the viscoelastic is expected toperform and the surgical technique being employed by the surgeon.

[0055] An appropriate buffer system (e.g., sodium phosphate, sodiumacetate or sodium borate) may be added to the compositions to prevent pHdrift under storage conditions.

[0056] Because all or a significant portion of the transitionalviscoelastics of the present invention may be left in the eye at theclose of surgery, these viscoelastics are uniquely adapted to serve thedual roles of viscosurgical tool and drug delivery device.

[0057] Ophthalmic drugs suitable for use in the compositions of thepresent invention include, but are not limited to: anti-glaucoma agents,such as beta-blockers including timolol, betaxolol, levobetaxolol, andcarteolol; miotics including pilocarpine; carbonic anhydrase inhibitors;prostaglandin analogues including latanoprost, travoprost, andbimatoprost; seratonergics; muscarinics; dopaminergic agonists;adrenergic agonists including apraclonidine and brimonidine;anti-infective agents including quinolones such as ciprofloxacin, andaminoglycosides such as tobramycin and gentamicin; non-steroidal andsteroidal anti-inflammatory agents, such as suprofen, diclofenac,ketorolac, rimexolone and tetrahydrocortisol; growth factors, such asEGF; immunosuppressant agents; and anti-allergic agents includingolopatadine. The ophthalmic drug may be present in the form of apharmaceutically acceptable salt, such as timolol maleate, brimonidinetartrate or sodium diclofenac. Compositions of the present invention mayalso include combinations of ophthalmic drugs, such as combinations of(i) a beta-blocker selected from the group consisting of betaxolol andtimolol, and (ii) a prostaglandin analogue selected from the groupconsisting of latanoprost; 15-keto latanoprost; fluprostenol isopropylester (especially1R-[1α(Z),2β(1E,3R*),3α,5α]-7-[3,5-dihydroxy-2-[3-hydroxy-4-[3-(trifluoromethyl)-phenoxy]-1-butenyl]cyclopentyl]-5-heptenoicacid, 1-methylethyl ester); and isopropyl[2R(1E,3R),3S(4Z),4R]-7-[tetrahydro-2-[4-(3-chlorophenoxy)-3-hydroxy-1-butenyl]-4-hydroxy-3-furanyl]-4-heptenoate.

[0058] In the event a pharmaceutical agent is added to the transitionalviscoelastics, such agents may have limited solubility in water andtherefore may require a surfactant or other appropriate co-solvent inthe composition. Such co-solvents typically include: polyethoxylatedcastor oils, Polysorbate 20, 60 and 80; Pluronic® F-68, F-84 and P-103(BASF Corp., Parsippany N.J., U.S.A.); cyclodextrin; or other agentsknown to those skilled in the art. Such co-solvents are typicallyemployed at a level of from about 0.01 to 2 wt. %. It may also bedesirable to add a pharmaceutically acceptable dye to the viscoelasticto improve visualization of the viscoelastic during surgery and/or tostain ocular tissue (especially the capsular bag during capsulorhexis incataract surgery) for improved visualization of such tissue. The use ofsuch dyes in conventional viscoelastics is described in WO 99/58160.Preferred dyes include trypan blue, trypan red, brilliant crysyl blue,and indo cyanine green. The concentration of the dye in the viscoelasticsolution will preferrably be between about 0.001 and 2 wt. %, and mostpreferably between about 0.01 and 0.1 wt %. However, it Will beappreciated by those skilled in the art that any such additive(pharmaceutical agents, co-solvents, or dyes) may only be employed tothe extent that they do not detrimentally affect the viscoelasticproperties of the compositions of the present invention.

[0059] The methods of the present invention may also involve the use ofvarious viscoelastic agents having different adherent or cohesiveproperties. Those skilled in the art will recognize that thecompositions of the present invention may be employed by the skilledsurgeon in a variety of surgical procedures.

[0060] Given the advantages of each type of viscoelastic, the surgeonmay employ is various viscoelastic compositions of the present inventionin a single surgical procedure. While the use of the transitionalviscoelastic of the present invention have not been disclosed for use insurgeries, U.S. Pat. No. 5,273,056 (McLaughlin et al.) discloses methodswhich exploit the use of compositions employing viscoelastics of varyingviscoelastic properties during a given ocular surgery, the entirecontents of which are incorporated herein by reference.

[0061] For example,. for portions of surgical procedures involvingphacoemulsification and/or irrigation/aspiration, e.g., cataractsurgery, it is generally preferable to use a viscoelastic agent thatpossesses relatively greater adherent properties and relatively lessercohesive properties. Such viscoelastic agents are referred to herein as“adherent” agents. The cohesiveness of a viscoelastic agent in solutionis thought to be dependent, at least in part, on the average molecularweight of that agent. At a given concentration, the greater themolecular weight, the greater the cohesiveness. Those portions ofsurgical procedures involving manipulation of delicate tissue aregenerally better served by viscoelastic agents that possess relativelygreater cohesive properties and relatively lesser adherent properties.Such agents are referred to herein as “cohesive” agents. For cohesiveagents such as these, which are being employed primarily for tissuemanipulation or maintenance purposes as opposed to protective purposes,a functionally desirable viscosity will be a viscosity sufficient topermit the skilled surgeon to use such agent as a soft tool tomanipulate or support the tissue of concern during the surgical step(s)being performed.

[0062] For other viscoelastic agents, which are being employed primarilyfor protective purposes (“adherent” agents) as opposed to tissuemanipulation purposes, a functionally desirable viscosity will be aviscosity sufficient to permit a protective layer of such agent toremain on the tissue or cells of concern during the surgical step(s)being performed. Such viscosity will typically be from about 3,000 cpsto about 60,000 cps (at shear rate of 2 sec⁻¹ and 25° C.), andpreferably will be about 40,000 cps. Such adherent agents are capable ofproviding the protective function previously discussed, yet are notprone to inadvertent removal, which could jeopardize the delicate tissuebeing protected. Unfortunately, this same characteristic makesaspiration of such adherent viscoelastics at the end of surgery (asrecommended for all such commercially available products in cataractsurgery), problematic for surgeons, and subjects the coated tissues totrauma during the removal procedure. A significant advantage of thetransitional viscoelastics of the present invention is that they may beleft in the surgical site at the close of surgery thereby avoidingunnecessary trauma to the affected soft tissues.

[0063] Preferred methods of the present invention will employ the use ofmultiple viscoelastics in a given surgical procedure, wherein at leastone of such viscoelastics is a transitional viscoelastic. In a mostpreferred embodiment of the invention, a transitional viscoelasticpossessing superior adherent properties is used in cataract surgery, atthe close of which some or all of it is left in situ and causes littleor no IOP spike.

[0064] The invention has been described by reference to certainpreferred embodiments; however, it should be understood that it may beembodied in other specific forms or variations thereof without departingfrom its spirit or essential characteristics. The embodiments describedabove are therefore considered to be illustrative in all respects andnot restrictive, the scope of the invention being indicated by theappended claims rather than by the foregoing description.

What is claimed is:
 1. A transitional viscoelastic composition for usein surgery, comprising a sterile, non-inflammatory, aqueous solutioncomprising kappa-carrageenan, potassium, and a second sulfatedpolysaccharide, such solution having a viscosity transition temperaturerange, wherein such solution exhibits a loss of viscosity of at least80% upon heating through such viscosity transition temperature range. 2.The composition of claim 1, wherein the viscosity transition temperaturerange is from 17-26° C. to 35-38° C.
 3. The composition of claim 2,wherein the viscosity transition temperature range is from about 25° C.to about 37° C., and wherein the second sulfated polysaccharide isselected from the group consisting of: iota-carrageenan, chondroitinsulfate, heparin, and combinations thereof.
 4. The composition of claim3, wherein the second sulfated polysaccharide is iota-carrageenan andthe weight ratio of the kappa-carrageenan to the iota-carrageenan isfrom about 2:3 to about 9:1.
 5. The composition of claim 4, wherein theweight ratio of kappa-carrageenan to iota-carrageenan is about 3:2. 6.The composition of claim 5, wherein the combined concentration of thekappa-carrageenan and the iota-carrageenan is about 0.8 wt %.
 7. Thecomposition of claim 3, wherein the second sulfated polysaccharide ischondroitin sulfate and the weight ratio of the kappa-carrageenan to thechondroitin sulfate is from about 4:5 to about 7:2.
 8. The compositionof claim 7, wherein the combined concentration of the kappa-carrageenanand the chondroitin sulfate is from about 0.9 to about 1.5 wt %.
 9. Atransitional viscoelastic composition for delivering an ophthalmic drugto an affected eye, comprising a sterile, aqueous solution comprisingkappa-carrageenan, potassium, and a second sulfated polysaccharide, suchsolution having a viscosity transition temperature range, wherein suchsolution exhibits a loss of viscosity of at least 80% upon warmingthrough such viscosity transition temperature range.
 10. The compositionof claim 9, wherein the viscosity transition temperature range is fromabout 25 to about 37° C. and wherein the ophthalmic drug is selectedfrom the group consisting of: anti-glaucoma agents; anti-infectiveagents; steroidal and non-steroidal anti-inflammatory agents; growthfactors; immunosuppressant agents; anti-allergy agents, and combinationsthereof.
 11. A method of protecting, manipulating or stabilizing tissuein an eye during surgery thereon, comprising instilling in the eye thetransitional viscoelastic composition of any of the foregoing claims.12. The method of claim 11, further comprising the step of allowing aprotecting or stabilizing effective amount of the transitionalviscoelastic to remain in the eye at the close of the surgery.